Chlororesistoflavins A and B, Chlorinated Benzopyrene Antibiotics Produced by the Marine-Derived Actinomycete Streptomyces sp. Strain EG32

Abstract

As part of a collaborative biomedical investigation of actinomycete bacteria isolated from sediments collected along the northern coast of Egypt (Mediterranean Sea), we explored the antibacterial metabolites from a bacterium identified as a Streptomyces sp., strain EG32. HPLC analysis and antibacterial testing against methicillin-resistant Staphylococcus aureus (MRSA) resulted in the identification of six compounds related to the resistoflavin and resistomycin class. Two of these metabolites were the chlorine-containing analogues chlororesistoflavins A (1) and B (2). The absolute configurations of the lone stereogenic center (C-11b) in these metabolites were assigned by analysis of their ECD spectra. Interestingly, the ECD spectrum of chlororesistoflavin A (1) shows a Cotton effect of the n−π* transition antipodal to that of the parent natural product, a consequence of 1,3-allylic strain induced by the adjacent bulky chlorine atom that distorts the coplanarity of the carbonyl group with the π-system. The chiroptical analysis thus resolves the paradox and uniformly aligns the configuration of all analogues as identical to that reported for natural resistoflavin. Chlororesistoflavins A (1) and B (2) exhibited antibacterial activity against MRSA with a minimum inhibitory concentration of 0.25 and 2.0 μg/mL, respectively.

Marine natural products

“…Two chlorinated, pentacyclic polyketides, chlororesistoflavins A 42 and B 43 , were reported from a marine sediment-derived Streptomyces sp., with 42 showing potent activity against MRSA (MIC 0.25 μg mL −1 ) which was eight-fold higher than that of the C-4 chloro isomer 43 (MIC 2.0 μg mL −1 ). 19 The two compounds also had remarkably different ECD spectra, with 42 displaying a Cotton effect near the n–π* transition of the C-10 carbonyl group which was opposite to that observed in other resistoflavins. This difference was attributed to allylic-1,3 strain imposed by the chlorine substitution at the C-11 position of the cyclohexadiene ring in 42 .…”

A Survey of Recently Discovered Naturally Occurring Organohalogen Compounds

“…The reduction product of 242, 5-chlororesistomycin (242a), is present in very small amounts in the organic extract of the culture medium and is counted as a natural product. 104 A South Korean marine sediment led to Streptomyces zhaozhouensis 208DD-064 and its two new fermentation products, streptopyrroles B (243) and C (244), along with four known analogues. Streptopyrrole B shows growth inhibition of several human cancer cell lines (GI 50 4.9−6.6 μM), and both B and C express some antibacterial activity (MIC 0.7−2.9 μM).…”

“…In the presence of light, both compounds undergo a formal two-electron reduction to afford the corresponding chlorxanthomycin. The reduction product of 242 , 5-chlororesistomycin ( 242a ), is present in very small amounts in the organic extract of the culture medium and is counted as a natural product . A South Korean marine sediment led to Streptomyces zhaozhouensis 208DD-064 and its two new fermentation products, streptopyrroles B ( 243 ) and C ( 244 ), along with four known analogues.…”

Secondary Metabolites from Marine-Derived Bacteria with Antibiotic and Antibiofilm Activities against Drug-Resistant Pathogens

“…For instance, when the chlorine atom is on C-11, as in 8 , its activity is comparable to that of the parent compound, i.e., resistoflavin. However, when the chlorine atom is on C-4, as in 9 , its activity is reduced when compared to resistoflavin [ 15 ].…”